Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)–skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.
Bibliographical noteFunding Information:
We thank R. Locksley for providing the reporter strains. We thank the Duke Light Microscopy Core Facility, especially Y. Gao, for their expertise and advice in light microscopy imaging. We thank the Flow Cytometry Shared Resource of the Duke Cancer Institute for their assistance with flow cytometry analysis. We also appreciate the help of M.-N. Huang in the design of the flow cytometry panel. The authors acknowledge the support of the US National Institutes of Health grants R01DK121032 and R01DK121969 to S.N.A.
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
ASJC Scopus subject areas
- Immunology and Allergy